Men1 maintains exocrine pancreas homeostasis in response to inflammation and oncogenic stress.

Autor:	Wasylishen AR; Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030., Sun C; Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030.; Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030., Chau GP; Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030., Qi Y; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030., Su X; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030., Kim MP; Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030., Estrella JS; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030., Lozano G; Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030; gglozano@mdanderson.org.; Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Mar 24; Vol. 117 (12), pp. 6622-6629. Date of Electronic Publication: 2020 Mar 10.
DOI:	10.1073/pnas.1920017117
Abstrakt:	A more comprehensive understanding of the molecular mechanisms underlying pancreatic diseases, including pancreatitis and cancer, is essential to improve clinical management. MEN1 has established roles in epigenetic regulation and tumor suppression in the endocrine pancreas; however, intriguing recent data suggest MEN1 may also function in the exocrine pancreas. Using physiologically relevant genetic mouse models, we provide direct evidence that Men1 is essential for exocrine pancreas homeostasis in response to inflammation and oncogenic stress. Men1 loss causes increased injury and impaired regeneration following acute caerulein-induced pancreatitis, leading to more severe damage, loss of the normal acinar compartment, and increased cytokeratin 19-positive metaplasias and immune cell infiltration. We further demonstrate the Men1 protein is stabilized in response to insult, and loss of Men1 is associated with the overexpression of proinflammatory Jund target genes, suggesting that loss of Men1-mediated repression of Jund activity is, at least in part, responsible for the impaired response. Finally, we demonstrate that Men1 loss significantly accelerates mutant Kras-dependent oncogenesis. Combined, this work establishes Men1 as an important mediator of pancreas homeostasis in vivo. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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